Depression has been considered to be the major psychiatric disease of the 20th century. The norepinephrine (NE) system is implicated in the etiology and treatment of depression, and several drugs that bind the NE transporter (NET) exhibit antidepressant properties. The NET has become an extremely important target of drug development research, and is also thought to be involved in the pathophysiology of several psychiatric disorders. Yet there have been few reports of promising NET radiotracers with characteristics appropriate for in vivo imaging studies. This project aims to develop improved NET radioligands labeled with carbon-11 and fluorine-18 for PET imaging, including ligands with higher affinity and selectivity but with lower lipophilicity than most previously reported probes. To accomplish this, a series of novel (R)-N-methyl 3-(substituted)-pyridinoxyl-3-phenylpropanamines (MPPA) and (S,S)-2-substituted- phenoxypyridinyl morpholines (PPYM), designed starting from the NET binding medications nisoxetine and reboxetine, will be synthesized. These compounds will be less lipophilic due to the inclusion of pyridine, pyrimidine and other heteroaromatic rings. The overall change in molecular size and weight are relatively small, and their NET affinity and selectivity should be preserved. In vitro evaluations of lipophilicity and affinity to human NET, dopamine transporters (DAT) and serotonin transporters (SERT) will be carried out. Those derivatives with appropriate in vitro characteristics will be labeled with either carbon-11 or fluorine-18 for in vivo evaluation in rats. The regional brain uptake over time will be measured, blocking studies will be performed to assess the degree of NET selective binding, and plasma and regional brain metabolite analyses will be carried out. The realization of improved PET NET radioligands will provide an important advance, allowing studies of NET density alterations associated with depression and other psychiatric disorders, and providing a much needed tool for drug dose versus occupancy studies in the human CNS. [unreadable] [unreadable]